tbuckley/cabot-search huggingface dataset:
Erectile Function and Oncologic Outcomes Following Open Retropubic and Robot-assisted Radical Prostatectomy: Results from the LAParoscopic Prostatectomy Robot Open Trial
Authors: Prasanna Sooriakumaran, Giovannalberto Pini, Tommy Nyberg, Maryam Derogar, Stefan Carlsson, Johan Stranne, Anders Bjartell, Jonas Hugosson, Gunnar Steineck, Peter N. Wiklund
Journal: European Urology (2017)
Neoadjuvant Treatment Approaches for Stage II–III Rectal Cancer
Authors: Steven Nurkin
Journal: Journal of the National Comprehensive Cancer Network (2023)

Excellent long-term outcomes are being achieved with contemporary treatment strategies for localized rectal cancer. A “watch-and-wait” nonoperative strategy seems to be a safe option for patients experiencing a complete clinical response. Total neoadjuvant therapy (TNT) has shown many advantages over standard chemoradiotherapy, although the optimal sequencing—with induction or consolidation chemotherapy—is still debated. The use of FOLFIRINOX can boost the benefit of TNT. Of note, in the small subset of patients whose tumors have mismatch repair deficiency, checkpoint inhibition has led to responses in most patients, eliminating the need for further treatment.
Abstract B014: ONECUT2 activates diverse drug-resistant phenotypes in prostate cancer
Authors: Chen Qian, Qian Yang, HyoYoung Kim, Yiwu Yan, Elahe Mostaghel, Leigh Ellis, Beatrice Knudsen, Salma Kaochar, Huihui Ye, Isla Garraway, Sungyong You, Michael Freeman
Journal: Cancer Research (2023)

Abstract BACKGROUND. Prostate cancer (PC) cells can escape from lineage confinement and be reprogrammed to a drug-resistant, high-plasticity state, however the mechanism underlying this process is not understood. Our group identified the HOX/CUT transcription factor ONECUT2 (OC2) as a mediator of metastatic castration-resistant PC (mCRPC) that can be inhibited with a novel family of small molecules. OC2 was shown to be a lineage plasticity driver that promotes neuroendocrine prostate cancer (NEPC). In this study, we sought to uncover the mechanism whereby OC2 exerts effects on lineage plasticity. METHODS. RNAseq, CUT&amp;RUNseq, scRNAseq, forced expression, shRNA, CRISPR-Cas9, co-precipitation/western blot, PCR, mutagenesis, human PC, PC models, computational modeling. RESULTS. We found that OC2 is capable of activating multiple androgen receptor- (AR)-indifferent, drug-resistant lineages, including programs not associated with NEPC, such as upregulation of the glucocorticoid receptor (GR). Consistent with the GR findings, OC2 regulated genes on the AR cistrome previously shown to be regulated by GR in CRPC, including KLK3/PSA. OC2 activated bivalent promoters of master regulator genes via epigenetic modification, and reprogramed multiple super-enhancers, including those associated with TMPRSS2 and SRRM4. OC2-expressing cells in human CRPC included populations that express AR, NE+/stem-like+, NE-/stem-like+, and “double negative” (NE-/AR-) phenotypes. OC2 also transcriptionally upregulated UDP-glucuronosyltransferase enzymes UGT2B15 and UGT2B17, which inactivate DHT, suggesting that the emergence of phenotypic plasticity also arises from AR suppression by ligand depletion. Consistent with this, low levels of androgen correlated with OC2 activation in human CRPC tumors. Enforced OC2 promoted both enzalutamide and docetaxel resistance in PC models. CONCLUSIONS. These findings identify OC2 as an upstream mediator of many lineage-defining factors that govern drug resistance, including those associated with adenocarcinoma. Because OC2 can be inhibited pharmacologically, these results suggest that suppressing this target may inhibit the emergence of a wide range of drug resistance mechanisms arising from loss of lineage confinement. Citation Format: Chen Qian, Qian Yang, HyoYoung Kim, Yiwu Yan, Elahe Mostaghel, Leigh Ellis, Beatrice Knudsen, Salma Kaochar, Huihui Ye, Isla Garraway, Sungyong You, Michael Freeman. ONECUT2 activates diverse drug-resistant phenotypes in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B014.
Abstract B024: Nuclear size and nuclear shape instability in prostate cancer epithelial cells during metastatic progression
Authors: Karen Cavassani, Edwin Posadas, Pai-Chi Teng, Sadaf Pustchi Pustchi, Minhyung Kim, Neil Bhowmick, Sungyong You, Michael Freeman, Leigh Ellis, Dolores Di Vizio, Hsian-Rong Tseng, Leland W. Chung, Susan Yao, Catherine Grasso
Journal: Cancer Research (2023)

Abstract Very small nuclear (vsn) circulating tumor cells (CTCs) are detected in a subgroup of metastatic, castration resistant prostate cancer (mCRPC) patients who develop visceral metastasis following intensive androgen receptor suppression. In addition, we have previously observed that nuclear shape instability (characterized by the loss and/or mis-localization of the nuclear envelop protein emerin) is present in human prostate cancer tissues, and in CTCs from patients with metastatic disease. Herein, we investigated the biological and clinical implications of the vsn phenotype in prostate CTCs. Patients with vsnCTCs had poor overall survival and low PSA response to androgen receptor suppression compared with non-vsnCTC patients. The vsnCTCs exhibited a loss/downregulation of emerin (EMD) and we found a direct correlation between emerin loss and nuclear size reduction in CTC from mCRPC patients. Further, in vitro studies revealed that the vsn phenotype was characterized by high invasive capacity, enhanced cellular plasticity, and resistance to AR target therapy. Finally, depletion of EMD in prostate tumor cells resulted in the vsn phenotype. Together, these findings demonstrate that the vsnCTC phenotype is characterized by deregulation of EMD expression, and the presence of these cells result in poor clinical outcomes in prostate cancer. Citation Format: Karen Cavassani, Edwin Posadas, Pai-Chi Teng, Sadaf Pustchi Pustchi, Minhyung Kim, Neil Bhowmick, Sungyong You, Michael Freeman, Leigh Ellis, Dolores Di Vizio, Hsian-Rong Tseng, Leland W. Chung, Susan Yao, Catherine Grasso. Nuclear size and nuclear shape instability in prostate cancer epithelial cells during metastatic progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B024.
Abstract B012: Genomic and epigenomic drivers of double-negative metastatic prostate cancer
Authors: Arian Lundberg, Meng Zhang, Rahul R. Aggarwal, Haolong Li, Li Zhang, Adam Foye, Martin Sjöström, Jonathan Chou, Kevin Chang, Thaidy Moreno-Rodriguez, Raunak Shrestha, Avi Baskin, Xiaolin Zhu, Alana S. Weinstein, Noah Younger, Joshi J. Alumkal, Tomasz M. Beer, Kim N. Chi, Christopher P. Evans, Martin Gleave, Primo N. Lara, Robert E. Reiter, Matthew B. Rettig, Owen N. Witte, Alexander W. Wyatt, Felix Y. Feng, Eric J. Small, David A. Quigley
Journal: Cancer Research (2023)

Abstract Systemic targeted therapy in prostate cancer is primarily focused on ablating androgen receptor (AR) signaling. Androgen deprivation therapy and second-generation AR-targeted therapy selectively favor the development of treatment-resistant subtypes of metastatic castration-resistant prostate cancer (mCRPC), defined by whether the tumor expresses either AR or neuroendocrine (NE) markers. Among the subtypes of mCRPC, the molecular drivers of double-negative (AR-/NE-) mCRPC are poorly defined. In this study, we comprehensively characterize genomic and epigenomic features of treatment-emergent mCRPC subtypes in 210 tumors by integrating matched RNA sequencing, whole-genome sequencing, and whole-genome bisulfite sequencing. We show that AR-/NE- tumors exhibit a clinically and molecularly distinct phenotype. Patients with AR-/NE- mCRPC tumors have the shortest survival, and these tumors preferentially harbor amplification of the chromatin remodeler CHD7 and loss of PTEN. We demonstrate that methylation changes in CHD7 candidate enhancers are linked to elevated CHD7 expression in AR-/NE+ tumors. Moreover, we use genome-wide methylation analysis to nominate the Krüppel-like factor gene KLF5 as a driver of the AR-/NE- phenotype and link its activity to loss of the tumor suppressor RB1. These observations reveal the aggressiveness of the AR-/NE- tumors and elucidate genomic and epigenomic drivers of mCRPC subtypes, which may facilitate the identification of novel therapeutic targets in this highly aggressive disease. Citation Format: Arian Lundberg, Meng Zhang, Rahul R. Aggarwal, Haolong Li, Li Zhang, Adam Foye, Martin Sjöström, Jonathan Chou, Kevin Chang, Thaidy Moreno-Rodriguez, Raunak Shrestha, Avi Baskin, Xiaolin Zhu, Alana S. Weinstein, Noah Younger, Joshi J. Alumkal, Tomasz M. Beer, Kim N. Chi, Christopher P. Evans, Martin Gleave, Primo N. Lara, Robert E. Reiter, Matthew B. Rettig, Owen N. Witte, Alexander W. Wyatt, Felix Y. Feng, Eric J. Small, David A. Quigley. Genomic and epigenomic drivers of double-negative metastatic prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B012.
Abstract B075: Anti-human LIV-1 antibody drug conjugate for treatment of metastatic prostate cancer
Authors: Xiaobei Zhao, Gang Chen
Journal: Cancer Research (2023)

Abstract In the worldwide male population, prostate cancer has the most frequent malignancy; out of all the cancer-related causes of deaths, it is also one of the most common. With the advance of new therapies of androgen receptor pathway inhibitors, patient survival rates have improved significantly. There are still tremendous unmet needs, however, for the patients with treat-refractory metastatic castration-resistant prostate cancer (mCRPC). LIV-1, also known as SLC39A6 or ZIP6, is a member of the zinc transporter family and was first identified as an estrogen-inducible gene in breast cancer. Previous studies with immunohistochemical (IHC) analysis showed that LIV-1 is expressed by estrogen receptor-positive (ER+), hormone-treated tumors (both primary and metastatic sites) and ER-/PR-/Her2- (triple-negative) breast cancers. These studies also showed that in healthy human tissues, LIV-1 expression is limited to hormonally-regulated organs (prostate, uterus, and breast). The broad expression of LIV-1 in prostate and breast cancer tumors in combination with the limited expression in vital organs makes LIV-1 an excellent target for an antibody-drug conjugate (ADC). We generated an ADC, BRY812, consisting of a humanized anti-LIV-1 mAb conjugated to monomethyl auristatin E (MMAE), via a novel conjugation method that prevents MMAE from coming off of the antibody during the circulation. The PK studies in rat and monkey showed that the free MMAE released from ADC is 1 to 2 log lower compared with approved ADCs prepared by the standard conjugation method. Low free MMAE concentration significantly lowers the risk of off target toxicity by the ADC. In vitro and in vivo studies demonstrated the antitumor activity of BRY812 for the treatment of prostate and ER+ and triple-negative breast cancers with a better safety profile and a larger therapeutic window. The humanized LIV-1 ADC, BRY812 is currently in preclinical toxicity studies and will advance to First-in-Human trials in April, 2023. Citation Format: Xiaobei Zhao, Gang Chen. Anti-human LIV-1 antibody drug conjugate for treatment of metastatic prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B075.
Abstract A074: In vivo modeling of castration-resistant prostate cancer in the immunodeficient SRG OncoRat
Authors: R. Grace Walton, Diane Begemann, Cynthia Dunn, Valeriya Steffey, Abigail Ross, Razoanul Haque, Fallon K. Noto
Journal: Cancer Research (2023)

Abstract Prostate cancer is the second most common cause of cancer-related deaths in American men. When locally targeted approaches fail, androgen deprivation therapy is administered to block androgen stimulated prostate cancer growth signals. Most tumors initially exhibit rapid and dramatic regression following androgen deprivation therapy. However, many patients treated with androgen deprivation therapy will have disease recurrence and develop castration-resistant prostate cancer (CRPC), which is highly metastatic with poor survival rates. To improve clinical options for CRPC, pre-clinical animal models that closely recapitulate the human disease course are an essential component of drug development. SRG OncoRats are highly immunocompromised Rag2/Il2rg double knockouts that lack mature B cells, T cells, and circulating NK cells. To establish an in vivo model of CRPC, we inoculated VCaP cells subcutaneously into the hind-flank of SRG OncoRats and monitored tumor growth. On Day 24 rats underwent orchiectomy and tumor growth was further monitored through Day 46. As seen with androgen deprivation therapy in humans, VCaP tumors initially regressed in the SRG OncoRats. However, VCaP tumors resumed growth 14 days after castration, faithfully modeling the progression of CRPC. After tumor regrowth, animals were enrolled into a therapeutic efficacy study that mimics the current clinical challenges in prostate cancer treatment. Citation Format: R. Grace Walton, Diane Begemann, Cynthia Dunn, Valeriya Steffey, Abigail Ross, Razoanul Haque, Fallon K. Noto. In vivo modeling of castration-resistant prostate cancer in the immunodeficient SRG OncoRat [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A074.
Abstract B007: New generation mTOR blocker sensitizes prostate cancer models to AR-targeting therapy
Authors: Shuang Li, Federico La Manna, Panagiotis Chouvardas, George Thalmann, Marianna Kruithof-de Julio
Journal: Cancer Research (2023)

Abstract Advanced stage prostate cancers (PCa) can develop bone metastasis, a lethal feature of castration-resistant prostate cancer (CRPC) for which no curative options are currently available. Androgen deprivation therapy (ADT) is the main therapeutic strategy for treating advanced PCa; patients with bone metastasis, however, are frequently developing resistance to ADT, progressing to CRPC. Dysregulation of the mTOR pathway has been linked with AR reactivation and with progression to CRPC, and mutations in targets of the PI3K/Akt/mTOR pathway are frequently found in CRPC patients. This study investigates the effect of synergistic AR and mTOR pathways blockade on therapy resistance in advanced PCa in vitro and in vivo. LNCaP and LAPC4 cells were treated in vitro with AR blockers (apalutamide, enzalutamide), mTOR blockers (rapamycin, everolimus, MLN0128 or Rapalink-1) or a combination of both blockers. Viability was measured in a timecourse from 1 to 10 days after drug administration using CellTiter Acqueous 96. To mimick ADT in vitro, cells were cultured for 7 days in charcoal-stripped serum in medium without dihydroxytestosterone or phenol red before the drug screening. Two already established PDX models of bone-metastatic PCa, BM18 and LAPC9 respectively androgen-dependent and -independent, were used to assess the effect of combined ADT and mTOR-targeting therapy in vivo. Both LNCaP and LAPC4 models showed a higher sensitivity to MLN0128 and Rapalink-1 compared to rapalogs, LAPC4 cells in particular were more sensitive than LNCaP cells to mTOR inhibitors. AR blockers were moderately effective and only at concentrations between 10 and 100 µM, when used alone. However, treatment with sublethal doses of Rapalink-1 (0.001-0.01 µM) sensitized both cell lines to 2- to 3-log fold lower concentrations of apalutamide. In vivo, treatment with Rapalink-1 alone significantly reduced the growth rate of LAPC9 PDX, while co-treatment with ADT and Rapalink-1 resulted in regression in this CRPC model, a result not achievable by either treatment alone. Treatment with Rapalink-1, while effectively reducing cell viability in vitro already when used alone, could sensitize the tested models to AR blockers, at clinically relevant concentrations. In vivo treatment with Rapalink-1 was well-tolerated and sufficient to control the growth of the BM18 PDX model. When used in combination with ADT, it could induce regression of the CRPC model LAPC9. Citation Format: Shuang Li, Federico La Manna, Panagiotis Chouvardas, George Thalmann, Marianna Kruithof-de Julio. New generation mTOR blocker sensitizes prostate cancer models to AR-targeting therapy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B007.
Abstract B029: Foxf2 activates antitumor immunity to repress the progression of prostate cancer by repressing Fgl1
Authors: Deyong Jia, Zhicheng Zhou, OhJoon Kwon, Li Xin
Journal: Cancer Research (2023)

Abstract Targeting immune suppressive mechanisms in the tumor microenvironment has revolutionized cancer treatment. Although immune checkpoint inhibition (ICI) has yielded meaningful responses across many cancer types, the ICI efficacy is still limited for prostate cancer. We generated a mouse model with prostate epithelial specific expression of Foxf2, a Forkhead box transcription factor. Foxf2 overexpression suppressed tumor growth in two mouse models for prostate cancer with prostate specific Pten deletion or TRAMP. Foxf2 expression strongly induced tumor cell-intrinsic immune responses by recruiting and activating CD8+ T cells and switching the polarization of macrophages from an immunosuppressive M2-like phenotype to a more inflammatory M1-like state in both syngeneic and autochthonous mouse prostate cancer models in an immunocompetent context. Furthermore, we showed that overexpression of Foxf2 in mouse and human prostate cells repressed the expression of FGL1, a major ligand of LAG-3 that mediates T cell suppression. In this study, we take a combination of bioinformatic, molecular, cellular, and genetic approaches and reveal that Foxf2 overexpression in prostate cancer suppresses tumor progression by activating antitumor immunity. Citation Format: Deyong Jia, Zhicheng Zhou, OhJoon Kwon, Li Xin. Foxf2 activates antitumor immunity to repress the progression of prostate cancer by repressing Fgl1 [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B029.
Abstract A083: Low dose abiraterone in prostate cancer - Safety, efficacy and pharmacoeconomic implications
Authors: Suryakanta Acharya
Journal: Cancer Research (2023)

Abstract Background and aim: Survival has improved in metastatic castration-resistant prostate cancer (mCRPC) because of the development of effective drugs such as abiraterone acetate, but universal accessibility to treatment is not always possible because of cost constraints in lower- and middle-income countries. Abiraterone in fasting state is the standard of care in mCRPC. Despite a large food effect, it was administered under fasting conditions in its pivotal trials. Recently, the National Comprehensive Cancer Network (NCCN) has included low-dose abiraterone (250 mg/day) with food as an alternative treatment option to full-dose abiraterone (1,000 mg/day) fasting. This translates to 75% cost reduction. This study aims to find safety, efficacy and pharmacoeconomic implications of low dose abiraterone in mCRPC. Materials and Methods: In this cohort study mCRPC Patients with progression were offered low dose abiraterone with low fat meal along with prednisone 5 mg twice daily. Prostate-specific antigen (PSA) was assessed monthly and toxicity assessment was made every week. Final PSA response (≥ 50% reduction) and toxicity assessment were done at 12 weeks. In case of grade IV toxicity (Anemia, Hypertension, Hypokalemia, Hypocalcemia – CTC AE V5.0) because of higher drug bioavailability, patient would be offered full dose abiraterone. 10 patients were offered low dose abiraterone in 2022. Results: 6 out of 10 patients achieved desired PSA response at 12 weeks which is a bit on higher side compared to standard dose abiraterone (recent literature). Fortunately, none of the patient developed grade IV toxicity. This finding was assuring, and no patient shifted to standard dosing. Conclusions: Low dose abiraterone (with low-fat breakfast) is noninferior to full dose abiraterone with respect to PSA metrics. Toxicity is the major thing to look at and given the pharmacoeconomic implications it’s imperative to adopt this strategy in places where affordability is the issue. Let the patients have something rather than nothing! Citation Format: Suryakanta Acharya. Low dose abiraterone in prostate cancer - Safety, efficacy and pharmacoeconomic implications [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A083.
Abstract A075: Characterizing novel aggressive prostate cancer subtypes associated with loss of chromosomes 8p and 16q
Authors: Gabriel A. Yette, James C. Costello, Scott D. Cramer
Journal: Cancer Research (2023)

Abstract Roughly 15% of the 268,490 men newly diagnosed with prostate cancer (PCa) will die from the disease. Pinpointing the drivers of aggressive PCa is the first step to improve patient outcomes. Correlative analyses have linked genetic aberrations, including copy number alterations due to loss of large genomic regions, to poor prostate cancer prognosis. Many groups have connected the loss of chromosome 8p and 16q to aggressive PCa, yet the genes on these regions responsible for aggressive phenotypes are unknown. Mining TCGA data, we identified minimum consensus deletions and associated gene expression with disease recurrence to nominate 48 genes on 8p and 58 genes on 16q for further study. We designed a pooled double knockout library to test all pairwise gene combinations of the nominated 8p-16q genes. Gene pairs will be targeted by 16 paired crRNA cassettes consisting of four crRNAs per gene and paired in all combinations. This library will be combined with stably expressing Cas12a prostate epithelial cell lines to screen for gene combinations that drive excessive cell proliferation. This will help pinpoint specific PCa tumor suppressors in combined 8p and 16q loss. Citation Format: Gabriel A. Yette, James C. Costello, Scott D. Cramer. Characterizing novel aggressive prostate cancer subtypes associated with loss of chromosomes 8p and 16q [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A075.